Method for coating medical devices

ABSTRACT

Medical devices, and in particular implantable medical devices, may be coated to minimize or substantially eliminate a biological organism&#39;s reaction to the introduction of the medical device to the organism or to treat a particular condition. A dip coating process is utilized to minimize waste. An aqueous latex polymeric emulsion is utilized to coat any medical device to a desired thickness by allowing for successive dipping and drying cycles. In addition, aqueous latex polymeric emulsions pose less of a chance of the bridging phenomenon associated with organic solvent based polymers.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for coating medical devices,and more particularly, to a process for dip coating medical deviceshaving complex configurations or geometries utilizing aqueous latexpolymeric emulsions.

2. Discussion of the Related Art

Stents, which are generally open tubular structures, have becomeincreasingly important in medical procedures to restore the function ofbody lumens. Stents are now commonly used in translumenial proceduressuch as angioplasty to restore an adequate blood flow to the heart.However, stents may stimulate foreign body reactions that result inthrombosis or restenosis. To avoid these complications, a variety ofpolymeric stent coatings and compositions have been proposed in theliterature, both to reduce the incidence of these or other complicationsor by delivering therapeutic compounds such as thrombolytics to thelumen to prevent thrombosis or restenosis. For example, stents coatedwith polymers containing thrombolytics such as heparin have beenproposed in the literature.

Stents are typically coated by a simple dip or spray coating of thestent with polymer or polymer and a pharmaceutical/therapeutic agent ordrug. These methods were acceptable for early stent designs that were ofopen construction fabricated from wires or from ribbons. Dip coatingwith relatively low coating weights (about four percent polymer) couldsuccessfully coat such stents without any problems such as excesscoating bridging, i.e. forming a film across the open space betweenstructural members of the device. This bridging is of particular concernwhen coating more modern stents that are of less open construction.Bridging of the open space (slots) is undesirable because it caninterfere with the mechanical performance of the stent, such asexpansion during deployment in a vessel lumen. Bridges may rupture uponexpansion and provide sites that activate platelet deposition bycreating flow disturbances in the adjacent hemodynamic environment, orpieces of the bridging film may break off and cause furthercomplications. Bridging of the open slots may also prevent endothelialcell migration, thereby complicating the endothelial cell encapsulationof the stent. The bridging problem is of particular concern in medicaldevices having complex configurations or designs, such as stents, whichcomprise a multiplicity of curved surfaces.

Similarly, spray coating can be problematic in that there is asignificant amount of spray lost during the spray process and many ofthe pharmaceutical agents that one would like to incorporate in thedevice are quire costly. In addition, in some cases it would bedesirable to provide coated stents with high levels of coating and drug.High concentration coatings (approximately fifteen percent polymer withadditional drug) are the preferred means to achieve high drug loading.Multiple dip coating has been described in the literature as a means tobuild thicker coatings on the stent. However, composition and phasedispersion of the pharmaceutical agents affect sustained release profileof the pharmaceutical agent. In addition, the application of multipledip coats from low concentration solutions often has the effect ofreaching a limiting loading level as an equilibrium state is reachedbetween the solution concentration and the amount of coating, with orwithout pharmaceutical agent, deposited on the stent. Thus there is acontinuing need for new and improved stent coating techniques.

Another potential problem associated with coating stents and otherimplantable medical devices having complex designs or configurations isthe use of organic based solvents. Presently, polymeric coatings areapplied from solutions of one or more polymers in one or more organicsolvents. These solvents do not permit repeated dipping to build up thedesired amount of coating as the solvent will re-dissolve the coatingapplied during the previous dipping. Accordingly, spin or spray coatingtechniques are utilized. However, as described above, this type ofcoating process may result in a significant amount of material lost.

Spray coating utilizing organic solvents generally involves dissolving apolymer or polymers and a therapeutic agent or agents in an organicsolvent or solvents. The polymer(s) and therapeutic agent(s) may bedissolved at the same time or at different times, for example, it may bebeneficial to add the therapeutic agent(s) just prior to coating becauseof the short shelf-life of the agent(s). Certain therapeutic agents maybe dissolved in organic solvents while others may not. For example,rapamycin may be mixed withpoly-(vinylidenefluoride)-co-hexafluoropropylene and dissolved in amixture of methyl ethyl ketone (MEK) and dimethylacetamide (DMAC) foruse as a coating on a stent to prevent or substantially minimizerestenosis. Water based therapeutic agents may not be dissolvable inorganic solvents, although it may be possible to disperse very finepowder form therapeutic agents in an organic solvent polymer emulsion.Therefore, whole classes of therapeutic agents may not be available foruse in local delivery applications on implantable medical devices.

In addition, organic solvents may be difficult to work with due to theirpotentially flammable or combustible nature.

Accordingly, there exists a need for a coating process that allows forthe safe, efficient, cost effective coating of medical devices for awide range of polymers and therapeutic drugs, agents and/or compounds.

SUMMARY OF THE INVENTION

The present invention overcomes the disadvantages associated withcoating medical devices, as briefly described above, by utilizing anaqueous latex emulsion of polymers and therapeutic drugs, agents and/orcompounds in a dip coating process.

In accordance with one aspect, the present invention is directed to amethod for coating medical devices. The method comprises the steps ofpreparing an aqueous latex polymeric emulsion, dipping a medical devicein the aqueous latex polymeric emulsion, drying the aqueous latexpolymeric emulsion on the medical device, and repeating the dipping anddrying steps until the aqueous latex polymeric emulsion coating reachesa predetermined thickness.

In accordance with another aspect, the present invention is directed toa method for coating medical devices. The method comprises the steps ofpreparing an aqueous latex polymeric emulsion, adding at least one drug,agent and/or compound, in therapeutic dosages, to the aqueous latexpolymeric emulsion for the treatment of a predetermined condition,dipping the medical device in the aqueous latex polymeric emulsion,including the at least one drug, agent and/or compound, drying theaqueous latex polymeric emulsion, including the at least one drug, agentand/or compound, on the medical device to form a coating thereon, andrepeating the dipping and drying steps until the aqueous latex polymericemulsion, including the at least one drug, agent and/or compound coatingreaches a predetermined thickness.

The method for dip coating medical devices in an aqueous latex polymericemulsion, which may or may not include therapeutic drugs, agents and/orcompounds, in accordance with the present invention provides a safe,efficient and effective process for coating medical devices havingsimple or complex configurations or designs. The dip coating processincludes preparing an aqueous latex polymeric emulsion from any numberof biocompatible monomers, adding drugs, agents and/or compounds intherapeutic dosages to the polymeric emulsion if desired to treat aspecific condition, dipping the medical device in the emulsion,including any drug, agent and/or compound added thereto, allowing thepolymeric emulsion to dry on the medical device thereby forming acoating thereon, and repeating the dipping and drying steps until thedesired coating thickness is achieved. The drug, agent and/or compoundmay be added to the emulsion as solid(s) or solution(s). The medicaldevice may be dried by allowing the water to evaporate or by utilizing adrying device such as a fan.

The method in accordance with the present invention minimizes waste.Spray coating of medical devices results in waste because of theoverspray phenomenon. This waste may result in significant material andmonetary losses, especially if drugs, agents and/or compounds areutilized. Desired coating thicknesses may also be achieved by utilizinga dip coating process with an aqueous latex polymeric emulsion. Inorganic based solvent polymeric emulsions, repeated dipping dissolvesthe previously laid down layers. The aqueous latex polymeric emulsion ofthe present invention enables multiple dippings without dissolving thematerial laid down during the prior dipping steps and thus build up acoating of desired weight or thickness. In addition, medical deviceshaving complex configurations or geometries, may be coated moreeffectively since aqueous latex polymeric emulsions are substantiallyless likely to bridge gaps between the structural members of the medicaldevices.

The method in accordance with the present invention is safe toimplement. Water based emulsions are safer to utilize because there islittle chance of fire or explosion. In addition, it is safer from thedisposal perspective. Organic based solvent polymeric emulsion disposalmust be done in accordance with strict environmental guidelines, whereaswater based polymeric emulsions are much more easily disposed of.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and advantages of the invention will beapparent from the following, more particular description of preferredembodiments of the invention, as illustrated in the accompanyingdrawings.

FIG. 1 is a flow chart of the method for coating medical devices inaccordance with the present invention.

FIG. 2 is a view along the length of a stent (ends not shown) prior toexpansion, showing the exterior surface of the stent and thecharacteristic banding pattern.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The local delivery of drug/drug combinations may be utilized to treat awide variety of conditions utilizing any number of medical devices, orto enhance the function and/or life of the medical device. For example,intraocular lenses, placed to restore vision after cataract surgery isoften compromised by the formation of a secondary cataract. The latteris often a result of cellular overgrowth on the lens surface and can bepotentially minimized by combining a drug or drugs with the device.Other medical devices which often fail due to tissue in-growth oraccumulation of proteinaceous material in, on and around the device,such as shunts for hydrocephalus, dialysis grafts, colostomy bagattachment devices, ear drainage tubes, leads for pace makers andimplantable defibrillators can also benefit from the device-drugcombination approach. Devices which serve to improve the structure andfunction of tissue or organ may also show benefits when combined withthe appropriate agent or agents. For example, improved osteointegrationof orthopedic devices to enhance stabilization of the implanted devicecould potentially be achieved by combining it with agents such asbone-morphogenic protein. Similarly other surgical devices, sutures,staples, anastomosis devices, vertebral disks, bone pins, sutureanchors, hemostatic barriers, clamps, screws, plates, clips, vascularimplants, tissue adhesives and sealants, tissue scaffolds, various typesof dressings, bone substitutes, intraluminal devices, and vascularsupports could also provide enhanced patient benefit using thisdrug-device combination approach. Essentially, any type of medicaldevice may be coated in some fashion with a drug or drug combinationwhich enhances treatment over use of the singular use of the device orpharmaceutical agent.

In addition to various medical devices, the coatings on these devicesmay be used to deliver therapeutic and pharmaceutic agents including:antiproliferative/antimitotic agents including natural products such asvinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine),paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide),antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents suchas G(GP) II_(b)/III_(a) inhibitors and vitronectin receptor antagonists;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes—dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);anti-inflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives i.e. aspirin; para-aminophenol derivativesi.e. acetominophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenicagents: vascular endothelial growth factor (VEGF), fibroblast growthfactor (FGF); angiotensin receptor blockers; nitric oxide donors;anti-sense oligionucleotides and combinations thereof; cell cycleinhibitors, mTOR inhibitors, and growth factor receptor signaltransduction kinase inhibitors; retenoids; cyclin/CDK inhibitors; HMGco-enzyme reductase inhibitors (statins); and protease inhibitors.

The present invention is directed to a method of dip coating medicaldevices in an aqueous latex (includes stable aqueous dispersions ofnatural rubber, synthetic rubber and vinyl polymers prepared by emulsionpolymerization) polymeric emulsion, which may or may not includetherapeutic drugs, agents and/or compounds. In utilizing a dip coatingprocess, waste is minimized as compared to a spray coating process.Also, by utilizing an aqueous latex polymeric emulsion, the dip coatingprocess may be repeated until the desired coating thickness is achieved.In other words, greater control over the weight and thickness of thecoating may be achieved. In addition, medical devices having complexconfigurations or geometries, for example, stents, may be coated moreeffectively since aqueous latex polymeric emulsions are substantiallyless likely to bridge gaps between the structural members of the medicaldevices as described above.

Referring to FIG. 1, there is illustrated a flow chart 100 of the methodfor coating medical devices. The dip coating process includes preparingan aqueous latex polymeric emulsion 102, adding drugs, agents and/orcompounds in therapeutic dosages to the polymeric emulsion, if desired104, dipping the medical device in the polymeric emulsion 106, allowingthe polymeric emulsion to dry on the medical device 108, determining ifthe coating is of the desired thickness 110, and repeating steps 106 to110 until the desired coating thickness is achieved. Typically, thecoating thickness is in the range from about four microns to about onehundred microns, and preferably in the range from about four microns toabout fifteen microns.

Although any number of biocompatible polymers may be utilized inaccordance with the present invention, the exemplary aqueous latexpolymeric emulsion is formed from two monomers, vinylidenefluoride andhexafluoropropylene. Each of these monomers are gases at atmosphericpressure; accordingly, the polymerization reactor is pressurized to apressure in the range from about five hundred fifty psi to about onethousand eight hundred psi during the polymerization process, whereinthe monomers are in the liquid state or phase. The monomers, in theliquid state, may be added to the water at the same time or at differenttimes. The monomers are added to the water in a predetermined ratio byweight. The monomer to water ratio may be in the range from about 5:95to about 35:65 and preferably about 25:75.

Polymerization is essentially the formation of compounds, usually ofhigh molecular weight, containing repeating structural units fromreactive intermediates or monomers. An initiator may be utilized toinitiate the polymerization process. Since this is a water basedpolymer, any number of water soluble initiators may be utilized,including hydrogen peroxide or partially water soluble peroxides and azocompounds. In the exemplary embodiment, ammonium persulfate is added tothe water and monomer mixture as an initiator. Water based initiatorswork by dissociating in water at elevated temperatures, controlled bythe polymerization reactor, to form free radicals. The free radicalsthen initiate polymerization by reacting with a monomer molecule,creating a new free radical, which then continues the polymerizationprocess until the monomer or monomers is/are is consumed.

Surfactants maintain molecules in suspension and prevents theconstituents of an emulsion from aggregating. Essentially, surfactantsact as emulsifying agents. It is possible to carry out thepolymerization process without the use of surfactants. If no surfactantis utilized, initiator residue on the polymer chain end acts as astabilizing agent to prevent polymer flocculation, i.e. aggregation. Ifa surfactant is utilized, any number of compounds may be utilized. Inthe exemplary embodiment, a blend of fluorinated surfactants, FluoradFC-26 and Zonyl TBS is utilized. Fluorinated surfactants are utilized inthe exemplary embodiment because of their compatibility with thefluorinated monomers. The surfactants work by forming micelles orsurfactant-rich regions, within the aqueous medium, which act as locifor polymer initiation. As the polymer particles grow, the surfactantmigrates to the outside of the polymer particles, with the hydrophobic(lacking affinity for water) end attached to the polymer and thehydrophilic (strong affinity for water) end extending into the aqueousmedium or water. This action tends to stabilize the polymer particlesthus preventing them from colliding and flocculating.

The combination of water, monomers, initiator and surfactants isconstantly stirred or agitated throughout the entire polymerizationprocess. Any suitable means may be utilized to agitate or stir themixture within the polymerization reactor. The polymerization processmay have a duration in the range from about two hours to about twentyhours. The polymerization process or reaction time is generally aboutseven hours depending on the desired level of conversion, initiatorconcentration and temperature. The polymerization reaction may beconducted at a temperature in the range from about seventy-five degreesC. to about one hundred ten degrees C. The length of the reaction timedetermines the ratio of monomers in the final polymer.

To increase the purity of the polymer, a nitrogen blanket is utilized inthe polymerization reactor. Nitrogen is pumped into the reaction chamberin order to eliminate as much oxygen as possible so that as littleoxygen as possible becomes incorporated into the polymer. Recalling thatthe polymerization reactor is pressurized to a pressure in the rangefrom about five hundred fifty psi to about eighteen hundred psi, thenitrogen blanket may be utilized for this prupose.

Once the desired reaction time is achieved, the contents of thepolymerization reactor are allowed to cool to ambient temperature andthe closed system of the reactor is vented to atmospheric pressure. Theventing of the polymerization reactor eliminates the nitrogen from thereactor and in the process removes any monomer residue. Monomer residueexists because one hundred percent conversion to polymer is difficult toachieve. Once the venting is complete, the polymerization reactorcontains an aqueous latex polymer emulsion which may be utilized to coatmedical devices.

A medical device may be dip coated in just thepoly(vinylidenefluoride)/hexafluoropropylene aqueous latex polymericemulsion or a mixture or dispersion of one or more therapeutic drugs,agents and/or compounds and the polymeric emulsion. Any number of drugs,agents and/or compounds, in therapeutic dosages, may be mixed with ordispersed in the polymeric emulsion. The drugs, agents and/or compoundsmay be in solid or liquid form. The drugs, agents and/or compounds maybe soluable in water, for example, heparin, or not soluable in water,for example, rapamycin, which is discussed in detail subsequently. Ifthe drugs, agents and/or compounds are not soluable in the aqueous latexpolymeric emulsion, they may be dispersed throughout the polymericemulsion by utilizing any number of well-known dispersion techniques.

The medical device, as described above, is dipped in the aqueous latexpolymeric emulsion, with or without the drugs, agents and/or compounds.The medical device is then removed from the polymeric emulsion whereinthe water evaporates and the remaining particulates forming the emulsionform a coating on the surfaces of the medical device and not in the gapsbetween sections of the device. As set forth above, the medical devicemay be assisted in drying through the use of fans, heaters, blowers orthe like. Once the medical device is “dry” the thickness of the coatingmay be determined utilizing any number of measuring techniques. If athicker coating is desired, the medical device may be repeatedly dippedand dried until the desired thickness is achieved. Upon successivedippings the water part of the emulsion will not re-dissolve the polymerthat dried on the surfaces of the medical device. In other words, repeatdipping will not cause the particulate matter to re-disperse in thewater. When organic solvents are utilized, as described above, repeatdipping cannot be successfully utilized.

The dip coating process of the present invention may be particularlyuseful in coating stents. Coronary stenting may be utilized toeffectively prevent vessel constriction after balloon angioplasty.However, inasmuch as stents prevent at least a portion of the restenosisprocess, a combination of drugs, agents and/or compounds which preventsmooth muscle cell proliferation, reduces inflammation and reducescoagulation or prevents smooth muscle cell proliferation by multiplemechanisms, reduces inflammation and reduces coagulation combined with astent may provide the most efficacious treatment for post-angioplastyrestenosis. The systematic use of drugs, agents and/or compounds incombination with the local delivery of the same or different drugs,agents and/or compounds may also provide a beneficial treatment option.

The local delivery of drug/drug combinations from a stent has thefollowing advantages; namely, the prevention of vessel recoil andremodeling through the scaffolding action of the stent and theprevention of multiple components of neointimal hyperplasia orrestenosis as well as a reduction in inflammation and thrombosis. Thislocal administration of drugs, agents or compounds to stented coronaryarteries may also have additional therapeutic benefit. For example,higher tissue concentrations of the drugs, agents or compounds may beachieved utilizing local delivery, rather than systemic administration.In addition, reduced systemic toxicity may be achieved utilizing localdelivery rather than systemic administration while maintaining highertissue concentrations. Also in utilizing local delivery from a stentrather than systemic administration, a single procedure may suffice withbetter patient compliance. An additional benefit of combination drug,agent, and/or compound therapy may be to reduce the dose of each of thetherapeutic drugs, agents or compounds, thereby limiting their toxicity,while still achieving a reduction in restenosis, inflammation andthrombosis. Local stent-based therapy is therefore a means of improvingthe therapeutic ratio (efficacy/toxicity) of anti-restenosis,anti-inflammatory, anti-thrombotic drugs, agents or compounds.

There are a multiplicity of different stents that may be utilizedfollowing percutaneous transluminal coronary angioplasty. Although anynumber of stents may be utilized in accordance with the presentinvention, for simplicity, one stent is described in exemplaryembodiments of the present invention. The skilled artisan will recognizethat any number of stents, constructed from any number of materials, maybe utilized in connection with the present invention. In addition, asstated above, other medical devices may be utilized.

A stent is commonly used as a tubular structure left inside the lumen ofa duct to relieve an obstruction. Commonly, stents are inserted into thelumen in a non-expanded form and are then expanded autonomously, or withthe aid of a second device in situ. A typical method of expansion occursthrough the use of a catheter-mounted angioplasty balloon which isinflated within the stenosed vessel or body passageway in order to shearand disrupt the obstructions associated with the wall components of thevessel and to obtain an enlarged lumen.

FIG. 2 illustrates an exemplary stent 200 which may be utilized inaccordance with an exemplary embodiment of the present invention. Theexpandable cylindrical stent 200 comprises a fenestrated structure forplacement in a blood vessel, duct or lumen to hold the vessel, duct orlumen open, more particularly for protecting a segment of artery fromrestenosis after angioplasty. The stent 200 may be expandedcircumferentially and maintained in an expanded configuration, that iscircumferentially or radially rigid. The stent 200 is axially flexibleand when flexed at a band, the stent 200 avoids any externallyprotruding component parts.

The stent 200 generally comprises first and second ends with anintermediate section therebetween. The stent 200 has a longitudinal axisand comprises a plurality of longitudinally disposed bands 202, whereineach band 202 defines a generally continuous wave along a line segmentparallel to the longitudinal axis. A plurality of circumferentiallyarranged links 204 maintain the bands 202 in a substantially tubularstructure. Essentially, each longitudinally disposed band 202 isconnected at a plurality of periodic locations, by a shortcircumferentially arranged link 204 to an adjacent band 202. The waveassociated with each of the bands 202 has approximately the samefundamental spatial frequency in the intermediate section, and the bands202 are so disposed that the wave associated with them are generallyaligned so as to be generally in phase with one another. As illustratedin the figure, each longitudinally arranged band 202 undulates throughapproximately two cycles before there is a link to an adjacent band 202.

The stent 200 may be fabricated utilizing any number of methods. Forexample, the stent 200 may be fabricated from a hollow or formedstainless steel tube that may be machined using lasers, electricdischarge milling, chemical etching or other means. The stent 200 isinserted into the body and placed at the desired site in an unexpandedform. In one exemplary embodiment, expansion may be effected in a bloodvessel by a balloon catheter, where the final diameter of the stent 200is a function of the diameter of the balloon catheter used.

It should be appreciated that a stent 200 in accordance with the presentinvention may be embodied in a shape-memory material, including, forexample, an appropriate alloy of nickel and titanium or stainless steel.Structures formed from stainless steel may be made self-expanding byconfiguring the stainless steel in a predetermined manner, for example,by twisting it into a braided configuration. In this embodiment afterthe stent 200 has been formed it may be compressed so as to occupy aspace sufficiently small as to permit its insertion in a blood vessel orother tissue by insertion means, wherein the insertion means include asuitable catheter, or flexible rod. On emerging from the catheter, thestent 200 may be configured to expand into the desired configurationwhere the expansion is automatic or triggered by a change in pressure,temperature or electrical stimulation.

The stent 200 may be coated with the aqueous latex polymeric emulsiondescribed above, and any number of drugs, agents and/or compounds intherapeutic dosage amounts. Rapamycin has been shown to significantlyreduce restenosis.

Rapamycin is a macrocyclic triene antibiotic produced by Streptomyceshygroscopicus as disclosed in U.S. Pat. No. 3,929,992. It has been foundthat rapamycin among other things inhibits the proliferation of vascularsmooth muscle cells in vivo. Accordingly, rapamycin may be utilized intreating intimal smooth muscle cell hyperplasia, restenosis, andvascular occlusion in a mammal, particularly following eitherbiologically or mechanically mediated vascular injury, or underconditions that would predispose a mammal to suffering such a vascularinjury. Rapamycin functions to inhibit smooth muscle cell proliferationand does not interfere with the re-endothelialization of the vesselwalls.

Rapamycin reduces vascular hyperplasia by antagonizing smooth muscleproliferation in response to mitogenic signals that are released duringan angioplasty induced injury. Inhibition of growth factor and cytokinemediated smooth muscle proliferation at the late G1 phase of the cellcycle is believed to be the dominant mechanism of action of rapamycin.However, rapamycin is also known to prevent T-cell proliferation anddifferentiation when administered systemically. This is the basis forits immunosuppresive activity and its ability to prevent graftrejection.

As used herein, rapamycin includes rapamycin and all analogs,derivatives and congeners that bind to FKBP12, and other immunophilinsand possesses the same pharmacologic properties as rapamycin includinginhibition of TOR.

Although the anti-proliferative effects of rapamycin may be achievedthrough systemic use, superior results may be achieved through the localdelivery of the compound. Essentially, rapamycin works in the tissues,which are in proximity to the compound, and has diminished effect as thedistance from the delivery device increases. In order to take advantageof this effect, one would want the rapamycin in direct contact with thelumen walls. Accordingly, in a preferred embodiment, the rapamycin isincorporated onto the surface of the stent or portions thereof.Essentially, the rapamycin is preferably incorporated into the stent200, illustrated in FIG. 2, where the stent 200 makes contact with thelumen wall.

Rapamycin may be incorporated onto or affixed to the stent in a numberof ways. In the exemplary embodiment, the rapamycin is directlyincorporated into the polymeric matrix and the stent 200 is dip coatedusing the process described above. The rapamycin elutes from thepolymeric matrix over time and enters the surrounding tissue. Therapamycin preferably remains on the stent for at least three days up toapproximately six months, and more preferably between seven and thirtydays.

As stated above, film forming or bridging across the open space betweenstructural members of the medical device is of particular concern in dipcoating processes. Complex shapes or geometries tend to facilitatebridging. For example, curvature in stent design tends to promote theformation of films. Film forming in the open spaces in stents may causepotential problems, including the prevention of tissue in-growth and therelease of embolic causing material during stent expansion. Water has ahigh surface tension and does not readily form bridging films.Accordingly, the aqueous latex polymeric emulsion of the presentinvention is significantly less likely to form bridging film in a dipcoating process.

Although shown and described is what is believed to be the mostpractical and preferred embodiments, it is apparent that departures fromspecific designs and methods described and shown will suggest themselvesto those skilled in the art and may be used without departing from thespirit and scope of the invention. The present invention is notrestricted to the particular constructions described and illustrated,but should be constructed to cohere with all modifications that may fallwithin the scope of the appended claims.

1. A method for coating medical devices comprising the steps of: (a)preparing an aqueous latex polymeric emulsion of vinylidenefluoride andhexafluoropropolyene; (b) dipping a medical device in the aqueous latexpolymeric emulsion; (c) drying the aqueous latex polymeric emulsion onthe medical device to form a coating thereon; and (d) repeating steps(b) and (c ), at least once, until the aqueous latex polymeric emulsioncoating reaches a predetermined thickness.
 2. The method for coatingmedical devices according to claim 1, wherein the step of mixingvinylidenefluoride and hexafluoropropylene in water comprises addingvinylidenefluoride and hexafluoropropylene to the water in anapproximately twenty-five to seventy-five ratio by weight.
 3. The methodfor coating medical devices according to claim 1, wherein the step ofdrying the aqueous latex polymeric emulsion on the medical device toform a coating thereon comprises allowing the water to evaporate fromthe aqueous latex polymeric emulsion thereby depositing a film on thesurface of the medical devices.
 4. The method for coating medicaldevices according to claim 1, wherein the step of repeating steps (b)and (c) until the aqueous latex polymeric emulsion coating reaches apredetermined thickness comprises creating a coating in the range fromabout four to about fifteen microns.
 5. A method for coating medicaldevices comprising the steps of: (a) preparing an aqueous latexpolymeric emulsion of vinylidenefluoride and hexafluoropropylene; (b)adding at least one drug, agent and/or compound, in therapeutic dosages,to the aqueous latex polymeric emulsion for the treatment of apredetermined condition; (c) dipping the medical device in the aqueouslatex polymeric emulsion, including the at least one drug, agent and/orcompound; (d) drying the aqueous latex polymeric emulsion, including theat least one drug, agent and/or compound, on the medical device to forma coating thereon; and (e) repeating steps (c) and (d), at least once,until the aqueous latex polymeric emulsion, including the at least onedrug, agent and/or compound coating reaches a predetermined thickness.6. The method for coating medical devices according to claim 5, whereinthe step of mixing vinylidenefluoride and hexafluoropropylene in watercomprises adding vinylidenefluoride and hexafluoropropylene to the waterin an approximately twenty-five to seventy-five ratio by weight.
 7. Themethod for coating medical devices according to claim 5, wherein thestep of adding at least one drug, agent and/or compound comprises addingan anti-proliferative.
 8. The method for coating medical devicesaccording to claim 7, wherein the step of adding at least one drug,agent and/or compound comprises adding rapamycin.
 9. The method forcoating medical devices according to claim 5, wherein the step of dryingthe aqueous latex polymeric emulsion, including the at least one drug,agent and/or compound, on the medical device to form a coating thereoncomprises allowing the water to evaporate from the aqueous latexpolymeric emulsion thereby depositing a film on the surface of themedical devices.
 10. The method for coating medical devices according toclaim 5, wherein the step of repeating steps (c) and (d) until theaqueous latex polymeric emulsion, including the at least one drug, agentand/or compound, coating reaches a predetermined thickness comprisescreating a coating in the range from about four to about fifteenmicrons.